During the past five years we have carried out studies, as part of this Center, that allowed us to defined and characterize the late phase of long- term potentiation (L-LTP). We have found that L-LTP appears to map onto long-term memory formation and we have characterized several molecular components necessary for memory formation. We then went on to show that age-related memory loss in mice is associated with an impairment of L-LTP and that drugs that act on this phase and reserve the physiological defect also reverses the age-related memory loss. To study more effectively the roles of genes in memory formation and memory disorders, we have developed methods for directing and regulating transgene expression in mouse brain, and for brain region specific ablation. We now propose to use these methods for generating new mouse models for Down's Syndrome (trisomy 21). In particular, we want to study the role of minibrain kinase (mnbK)- a gene in the critical Down's syndrome region of chromosome 21-in the cognitive defect of Down's syndrome. We plan to generate mice with regulated expression, in the hippocampus, of the minibrain kinase transgene, as well as mice with hippocampal specific knockout of the minibrain gene In so doing we plan to examine the role of the minibrain kinase in the memory defect, the developmental time course during which expression of the kinase produces, the physiological consequences of minibrain expression in the brain, as well as possible pharmacologic approaches to blocking the action of the kinase. We also propose to use a mouse model to explore the role of the minibrain kinase in the early onset of Alzheimer's disease seen in patients with Down's syndrome. As potential links to Alzheimer's disease we propose. to explore potential substrates for the minibrain kinase.